Relapsing Remitting Multiple Sclerosis
Conditions
Keywords
Multiple sclerosis, estrogen, estriol, progesterone
Brief summary
This is a double-blinded, placebo controlled study of estriol pills versus placebo pills in relapsing remitting multiple sclerosis. The study treatment will be an added on to Copaxone injections in all subjects. The primary outcome measure is a reduction in relapses.
Detailed description
Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy. This proposal will establish whether oral treatment with estriol, the major estrogen of pregnancy, induces a decrease in relapses in relapsing remitting multiple sclerosis (RRMS) subjects when used in combination with injectable Copaxone. Previously, in a pilot study, it has been demonstrated that treatment of RRMS subjects with oral estriol for six months resulted in a significant reduction in gadolinium enhancing lesions on serial brain MRIs (Annals of Neurology, 2002; 52:421-428) and caused a favorable shift in immune responses (Journal of Immunology, 2003; 171:6267-6274). This is an add-on study aiming to extend these previous findings by treating longer and focusing on clinical outcomes. The combination of Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a double blind trial. The duration of treatment will be two years and the primary outcome measure will be relapse rate. Other outcomes will include disability measures and brain MRI outcomes. Safety measures (blood tests and gynecologic evaluations) will also be followed and correlations will be made between serum estriol levels with efficacy and safety. The overall goal of this study will be the development of a new oral treatment, estriol, for RRMS.
Interventions
Sponsors
Washington University School of Medicine
University of Texas Southwestern Medical Center
Ohio State University
University of Medicine and Dentistry of New Jersey
University of Chicago
University of Utah
Johns Hopkins University
University of Kansas Medical Center
University of Minnesota
Mayo Clinic
University of Colorado, Denver
University of New Mexico
University of Pennsylvania
Dartmouth-Hitchcock Medical Center
National Multiple Sclerosis Society
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of relapsing remitting multiple sclerosis * At least one relapse in the last two years
Exclusion criteria
* Patients treated in the past with total lymphoid irradiation, monoclonal antibody, T cell vaccination, cladribine, bone marrow transplantation, azathioprine, cyclophosphamide, methotrexate, mitoxantrone, cyclosporin or Tysabri * Clinically significant diseases other than multiple sclerosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Relapse, Annualized Relapse Rate | 24 months | A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Event, Annualized Relapse Rate | 24 months | Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner. |
| Confirmed Relapse, Probability of First Relapse | 24 months | — |
| Relapse Event, Probability of First Relapse Event | 24 months | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Relapse, Annualized Relapse Rate | 12 months | A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection. |
| Relapse Event, Annualized Relapse Rate | 12 months | Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Estriol Capsules Plus Copaxone Injections Estriol: Estriol 8 mg capsule, once per day, duration of treatment is 2 years | 82 |
| Placebo Capsules Plus Copaxone Injections Placebo: Placebo capsule, once a day, treatment duration is 2 years | 76 |
| Total | 158 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 |
| Overall Study | Lack of Efficacy | 4 | 4 |
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Other | 1 | 2 |
| Overall Study | Patient refusal | 8 | 4 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Capsules Plus Copaxone Injections | Estriol Capsules Plus Copaxone Injections | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 76 Participants | 82 Participants | 158 Participants |
| Age, Continuous | 37.1 years STANDARD_DEVIATION 7.3 | 37.7 years STANDARD_DEVIATION 7.6 | 37.4 years STANDARD_DEVIATION 7.45 |
| Region of Enrollment United States | 76 participants | 82 participants | 158 participants |
| Sex: Female, Male Female | 76 Participants | 82 Participants | 158 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 76 / 82 | 67 / 76 |
| serious Total, serious adverse events | 8 / 82 | 10 / 76 |
Outcome results
Primary
Confirmed Relapse, Annualized Relapse Rate
A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection.
Time frame: 24 months
Population: Included all as intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Estriol Capsules Plus Copaxone Injections | Confirmed Relapse, Annualized Relapse Rate | 0.25 relapses per year |
| Placebo Capsules Plus Copaxone Injections | Confirmed Relapse, Annualized Relapse Rate | 0.37 relapses per year |
p-value: 0.07795% CI: [0.37, 1.05]negative binomial regression
Secondary
Confirmed Relapse, Probability of First Relapse
Time frame: 24 months
Population: All included as intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Estriol Capsules Plus Copaxone Injections | Confirmed Relapse, Probability of First Relapse | 33.3 probability of relapse at 24 months |
| Placebo Capsules Plus Copaxone Injections | Confirmed Relapse, Probability of First Relapse | 42.9 probability of relapse at 24 months |
p-value: 0.09695% CI: [0.36, 1.09]negative binomial regression
Secondary
Relapse Event, Annualized Relapse Rate
Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
Time frame: 24 months
Population: Included all as intention to treat.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Estriol Capsules Plus Copaxone Injections | Relapse Event, Annualized Relapse Rate | 0.32 relapses per year |
| Placebo Capsules Plus Copaxone Injections | Relapse Event, Annualized Relapse Rate | 0.46 relapses per year |
p-value: 0.09895% CI: [0.39, 1.08]negative binomial regression
Secondary
Relapse Event, Probability of First Relapse Event
Time frame: 24 months
Population: Included all as intention to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Estriol Capsules Plus Copaxone Injections | Relapse Event, Probability of First Relapse Event | 40.5 probability of relapse event at 24 mo |
| Placebo Capsules Plus Copaxone Injections | Relapse Event, Probability of First Relapse Event | 46.9 probability of relapse event at 24 mo |
p-value: 0.17995% CI: [0.42, 1.17]negative binomial regression
Other Pre-specified
Confirmed Relapse, Annualized Relapse Rate
A confirmed relapse was defined as new neurological symptoms or worsening of pre-existing symptoms, lasting at least 48 hours in a subject who had been neurologically stable or improving in the previous 30 days, accompanied by objective change in the neurological examination (worsening of 0.5 points on the EDSS or worsening by 1.0 or more points on the pyramidal, cerebellar, brainstem or visual functional system scores), not due to fatigue alone and not associated with fever or infection.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Estriol Capsules Plus Copaxone Injections | Confirmed Relapse, Annualized Relapse Rate | 0.25 relapses per year |
| Placebo Capsules Plus Copaxone Injections | Confirmed Relapse, Annualized Relapse Rate | 0.48 relapses per year |
p-value: 0.01695% CI: [0.28, 0.88]negative binomial regression
Other Pre-specified
Relapse Event, Annualized Relapse Rate
Met all criteria for relapse except not confirmed to have increase in EDSS by an independent examiner.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Estriol Capsules Plus Copaxone Injections | Relapse Event, Annualized Relapse Rate | 0.33 relapses per year |
| Placebo Capsules Plus Copaxone Injections | Relapse Event, Annualized Relapse Rate | 0.61 relapses per year |
p-value: 0.01295% CI: [0.31, 0.86]negative binomial regression